LOW SWELL, LONG-LIVED HYDROGEL SEALANT

• US 20100015231A1
• Filed: 07/06/2009
• Published: 01/21/2010
• Est. Priority Date: 07/17/2008
• Status: Abandoned Application

• Current Assignee: Actamax Surgical Materials, LLC (DSM-Firmenich AG)
• Original Assignee: E. I. du Pont de Nemours and Company (Corteva, Inc.)
• Inventors: LU, Helen S. M.
• Application Number:
  US12/497,729
• Publication Number:
  US 20100015231A1
• Time in Patent Office: Days
• US Class Current: 424/488
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61L 24/08 Polysaccharides A61L24/043 takes precedence

Abstract

A low swell, long-lived hydrogel sealant formed by reacting a highly oxidized polysaccharide containing aldehyde groups with a multi-arm amine is described. The hydrogel sealant may be particularly suitable for applications requiring low swell and slow degradation, for example, ophthalmic applications such as sealing wounds resulting from trauma such as corneal lacerations, or from surgical procedures such as vitrectomy procedures, cataract surgery, LASIK surgery, glaucoma surgery, and corneal transplants; neurosurgery applications, such as sealing the dura; and as a plug to seal a fistula or the punctum. The low swell, long-lived hydrogel sealant may also be useful as a tissue sealant and adhesive, and as an anti-adhesion barrier.

Claims

1. A kit comprising:

a) a first aqueous solution or dispersion comprising at least one highly oxidized polysaccharide containing aldehyde groups, said highly oxidized polysaccharide having a weight-average molecular weight of about 1,000 to about 1,000,000 Daltons and an equivalent weight per aldehyde group of about 65 to about 85 Daltons, wherein said first aqueous solution or dispersion contains said highly oxidized polysaccharide at a concentration of 6% to about 40% by weight; and

b) a second aqueous solution or dispersion comprising at least one water-dispersible, multi-arm amine wherein at least three of the arms are terminated by at least one primary amine group, said multi-arm amine having a number-average molecular weight of about 450 to about 200,000 Daltons, wherein said second aqueous solution or dispersion contains said multi-arm amine at a concentration of about 5% to about 70% by weight;

provided that;

(i) if the concentration of the highly oxidized polysaccharide in the first aqueous solution or dispersion is equal to or greater than 6 wt % but less than 8 wt %, the equivalent weight per aldehyde group of the highly oxidized polysaccharide is about 65 to about 70 Daltons;

(ii) if the concentration of the highly oxidized polysaccharide in the first aqueous solution or dispersion is equal to or greater than 8 wt % to about 40 wt %, the equivalent weight per aldehyde group of the highly oxidized polysaccharide is about 65 to about 85 Daltons.

2. The kit according to claim 1 wherein the polysaccharide is selected from the group consisting of dextran, starch, agar, cellulose, and hyaluronic acid.

3. The kit according to claim 1 wherein the water-dispersible, multi-arm amine is selected from the group consisting of amino-terminated star polyethylene oxides, amino-terminated dendritic polyethylene oxides, amino-terminated comb polyethylene oxides, amino-terminated star polypropylene oxides, amino-terminated dendritic polypropylene oxides, amino-terminated comb polypropylene oxides, amino-terminated star polyethylene oxide-polypropylene oxide copolymers, amino-terminated dendritic polyethylene oxide-polypropylene oxide copolymers, amino-terminated comb polyethylene oxide-polypropylene oxide copolymers, polyoxyalkylene triamines, amino-terminated dendritic polyamidoamines, and multi-arm branched end amines.

4. The kit according to claim 1 wherein the polysaccharide is dextran and the water-dispersible, multi-arm amine is a multi-arm polyethylene glycol amine.

5. The kit according to claim 1 further comprising at least one multi-functional amine having one or more primary amine groups, wherein said multi-functional amine is contained in at least one of the following:

a) the first aqueous solution or dispersion;

b) the second aqueous solution or dispersion;

c) a third solution.

6. A dried hydrogel formed by a process comprising the steps of:

a) combining (i) a first solution or dispersion comprising at least one highly oxidized polysaccharide containing aldehyde groups in a first solvent, said oxidized polysaccharide having a weight-average molecular weight of about 1,000 to about 1,000,000 Daltons and an equivalent weight per aldehyde group of about 65 to about 85 Daltons, wherein said first solution or dispersion contains said highly oxidized polysaccharide at a concentration of 6% to about 40% by weight;

with (ii) a second solution or dispersion comprising at least one water-dispersible, multi-arm amine in a second solvent, wherein at least three of the arms of said multi-arm amine are terminated by at least one primary amine group, said multi-arm amine having a number-average molecular weight of about 450 to about 200,000 Daltons, wherein said second solution or dispersion contains said multi-arm amine at a concentration of about 5% to about 70% by weight, to form a hydrogel, wherein the first solvent is either the same as or different from the second solvent; and

b) treating the hydrogel to remove at least a portion of said first solvent and said second solvent to form the dried hydrogel;

provided that;

(i) if the concentration of the highly oxidized polysaccharide in the first solution or dispersion is equal to or greater than 6 wt % but less than 8 wt %, the equivalent weight per aldehyde group of the highly oxidized polysaccharide is about 65 to about 70 Daltons;

(ii) if the concentration of the highly oxidized polysaccharide in the first solution or dispersion is equal to or greater than 8 wt % to about 40 wt %, the equivalent weight per aldehyde group of the highly oxidized polysaccharide is about 65 to about 85 Daltons.

7. The dried hydrogel according to claim 6 wherein said dried hydrogel is in the form of a film.

8. The dried hydrogel according to claim 6 wherein the process further comprises the step of comminuting the dried hydrogel to form finely divided particles.

9. The dried hydrogel according to claim 6 wherein the polysaccharide is selected from the group consisting of dextran, starch, agar, cellulose, and hyaluronic acid.

10. The dried hydrogel according to claim 6 wherein the water-dispersible, multi-arm amine is selected from the group consisting of amino-terminated star polyethylene oxides, amino-terminated dendritic polyethylene oxides, amino-terminated comb polyethylene oxides, amino-terminated star polypropylene oxides, amino-terminated dendritic polypropylene oxides, amino-terminated comb polypropylene oxides, amino-terminated star polyethylene oxide-polypropylene oxide copolymers, amino-terminated dendritic polyethylene oxide-polypropylene oxide copolymers, amino-terminated comb polyethylene oxide-polypropylene oxide copolymers, polyoxyalkylene triamines, amino-terminated dendritic polyamidoamines, and multi-arm branched end amines.

11. The dried hydrogel according to claim 6 wherein the polysaccharide is dextran and the multi-arm amine is a multi-arm polyethylene glycol amine.

12. The dried hydrogel according to claim 6 wherein the first solvent and the second solvent are water.

13. A method for applying a coating to an anatomical site on tissue of a living organism comprising:

applying to the site (a) a first aqueous solution or dispersion comprising at least one highly oxidized polysaccharide containing aldehyde groups, said highly oxidized polysaccharide having a weight-average molecular weight of about 1,000 to about 1,000,000 Daltons and an equivalent weight per aldehyde group of about 65 to about 85 Daltons, wherein said first aqueous solution or dispersion contains said highly oxidized polysaccharide at a concentration of 6% to about 40% by weight;

followed by (b) a second aqueous solution or dispersion comprising at least one water-dispersible, multi-arm amine wherein at least three of the arms are terminated by at least one primary amine group, said multi-arm amine having a number-average molecular weight of about 450 to about 200,000 Daltons, wherein said second aqueous solution or dispersion contains said multi-arm amine at a concentration of about 5% to about 70% by weight, or

applying (b) followed by (a) and mixing (a) and (b) on the site, or

premixing (a) and (b) to form a mixture and applying said mixture to the site;

provided that;

(i) if the concentration of the highly oxidized polysaccharide in the first aqueous solution or dispersion is equal to or greater than 6 wt % but less than 8 wt %, the equivalent weight per aldehyde group of the highly oxidized polysaccharide is about 65 to about 70 Daltons;

(ii) if the concentration of the highly oxidized polysaccharide in the first aqueous solution or dispersion is equal to or greater than 8 wt % to about 40 wt %, the equivalent weight per aldehyde group of the highly oxidized polysaccharide is about 65 to about 85 Daltons.

14. The method according to claim 13 wherein the polysaccharide is dextran and the multi-arm amine is a multi-arm polyethylene glycol amine.

15. A composition comprising the reaction product of:

a) a first aqueous solution or dispersion comprising at least one highly oxidized polysaccharide containing aldehyde groups, said highly oxidized polysaccharide having a weight-average molecular weight of about 1,000 to about 1,000,000 Daltons and an equivalent weight per aldehyde group of about 65 to about 85 Daltons, wherein said first aqueous solution or dispersion contains said highly oxidized polysaccharide at a concentration of 6% to about 40% by weight; and

b) a second aqueous solution or dispersion comprising at least one water-dispersible, multi-arm amine wherein at least three of the arms are terminated by at least one primary amine group, said multi-arm amine having a number-average molecular weight of about 450 to about 200,000 Daltons, wherein said second aqueous solution or dispersion contains said multi-arm amine at a concentration of about 5% to about 70% by weight;

provided that;

(i) if the concentration of the highly oxidized polysaccharide in the first aqueous solution or dispersion is equal to or greater than 6 wt % but less than 8 wt %, the equivalent weight per aldehyde group of the highly oxidized polysaccharide is about 65 to about 70 Daltons;

(ii) if the concentration of the highly oxidized polysaccharide in the first aqueous solution or dispersion is equal to or greater than 8 wt % to about 40 wt %, the equivalent weight per aldehyde group of the highly oxidized polysaccharide is about 65 to about 85 Daltons.

16. The composition according to claim 15 wherein the polysaccharide is selected from the group consisting of dextran, starch, agar, cellulose, and hyaluronic acid.

17. The composition according to claim 15 wherein the water-dispersible multi-arm amine is selected from the group consisting of amino-terminated star polyethylene oxides, amino-terminated dendritic polyethylene oxides, amino-terminated comb polyethylene oxides, amino-terminated star polypropylene oxides, amino-terminated dendritic polypropylene oxides, amino-terminated comb polypropylene oxides, amino-terminated star polyethylene oxide-polypropylene oxide copolymers, amino-terminated dendritic polyethylene oxide-polypropylene oxide copolymers, amino-terminated comb polyethylene oxide-polypropylene oxide copolymers, polyoxyalkylene triamines, amino-terminated dendritic polyamidoamines, and multi-arm branched end amines.

18. The composition according to claim 15 wherein the polysaccharide is dextran and the water-dispersible, multi-arm amine is a multi-arm polyethylene glycol amine.